Miyatsu Miriu, Sukhbaatar Ariunbuyan, Mishra Radhika, Dorai Arunkumar, Mori Shiro, Kodama Tetsuya
Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4‑1 Seiryo, Aoba, Sendai, Miyagi, 980‑8575, Japan.
Division of Oral and Maxillofacial Oncology and Surgical Sciences, Graduate School of Dentistry, Tohoku University, 4‑1 Seiryo, Aoba, Sendai, Miyagi, 980‑8575, Japan.
Sci Rep. 2025 May 8;15(1):16037. doi: 10.1038/s41598-025-99602-8.
Systemic chemotherapy is a common method for treatment of metastatic lymph nodes (LNs), but it has low tissue selectivity and high toxicity. Lymphatic drug delivery system (LDDS) is a novel approach to treat and prevent LN metastases. In a previous study, it was found that the increase of osmotic pressure with varied viscosity of the drug reagent enhances drug retention in the LNs. Here, we optimized the administration conditions to achieve a long-term therapeutic response by varying the dosages and injection rate, using the optimized osmotic pressure and varied viscosity of drug reagent for LDDS. A metastatic LN mouse model was created with MXH10/Mo/lpr mice. Luciferase labelled FM3A mouse mammary carcinoma cells were inoculated in subiliac LN (SiLN) to induce metastasis to the proper axillary LN (PALN). 4 days post tumor cell inoculation, carboplatin (CBDCA) was injected into the tumor-bearing SiLN under different administration conditions. Superior drug retention was observed in the group that received two-doses of CBDCA solution adjusted to an osmotic pressure and viscosity of 1897 kPa and 12 mPa·s, at an injection rate of 10 µL/min. Furthermore, this effect persisted for 42 days. This effect was accompanied by an upregulated expression of CD8, IL-12a, and IFN-γ in the spleen. These results suggest that dual-dose administration at 10 µL/min with hyper-osmotic and high viscosity formulation is optimal and can improve the long-term therapeutic efficacy of LN metastasis.
全身化疗是治疗转移性淋巴结（LNs）的常用方法，但它的组织选择性低且毒性高。淋巴药物递送系统（LDDS）是一种治疗和预防LN转移的新方法。在先前的一项研究中，发现随着药物试剂粘度变化而导致的渗透压升高可增强药物在LNs中的滞留。在此，我们通过改变剂量和注射速率来优化给药条件，以实现长期治疗反应，使用优化的渗透压和不同粘度的药物试剂用于LDDS。用MXH10/Mo/lpr小鼠建立转移性LN小鼠模型。将荧光素酶标记的FM3A小鼠乳腺癌细胞接种于髂下淋巴结（SiLN），以诱导转移至腋窝正位淋巴结（PALN）。肿瘤细胞接种后4天，在不同给药条件下将卡铂（CBDCA）注入荷瘤SiLN。在以10 μL/min的注射速率接受两剂调整至渗透压为1897 kPa和粘度为12 mPa·s的CBDCA溶液的组中观察到了更好的药物滞留。此外，这种效果持续了42天。这种效果伴随着脾脏中CD8、IL-12a和IFN-γ表达的上调。这些结果表明，以10 μL/min的速率进行双剂量给药，采用高渗和高粘度制剂是最佳的，并且可以提高LN转移的长期治疗效果。
